Category Archives: clamp

Dopamine regulates systemic glucose metabolism in humans

In Four. EPIC. Experiments (ter Horst et al., 2018)

Tl;dr: sunlight & breakfast in the morning.

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Dopamine receptors are downregulated in obese patients and are restored in long-term weight loss patients after bariatric surgery. It’s better to get your dopamine hit via sunlight than sugar duh.

This is some amazing science.

 

 

Experiment 1. 50-year old dude with severe OCD gets diagnosed with type 2 diabetes and is only able to get his glucose under control with metformin and 226 IU insulin. At 53, his OCD is treated with deep brain stimulation (DBS). His insulin requirements declined to 180 IU. He didn’t lose weight but went off quetiapine, so maybe coincidence because: 1. quetiapine is diabetogenic; and 2. DBS induces dopamine release.

Two-step hyperinsulinemic euglycemic clamp when DBS is turned off and turned on. BOOM! When it’s on, lower fasting insulin, and better insulin-induced suppression of liver glucose output, free fatty acids, & muscle glucose disposal! DBS improved insulin sensitivity in liver, adipose, and skeletal muscle.

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Cycloset (bromocriptine)

 

 

Go for a walk.

And #eTRF.

 

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Ketosis in an evolutionary context

Humans are unique in their remarkable ability to enter ketosis.  They’re also situated near the top of the food chain.  Coincidence?

During starvation, humans rapidly enter ketosis; they do this better than king penguins, and bears don’t do it at all.

Starvation ketosis

 

Starvation ketosis

Humans maintain a high level of functionality during starvation.  We can still hunt & plan; some would even argue it’s a more finely tuned state, cognitively.  And that’s important, because if we became progressively weaker and slower, chances of acquiring food would rapidly decline.

Perhaps this is why fasting bears just sleep most of the time: no ketones = no bueno..?

Observation: chronic ketosis is relatively rare in nature. This doen’t mean animals evolved a protective  mechanism against ketosis.

 

 

Animals with a low brain/carcass weight ratio (ie, small brain) don’t need it. Babies and children have a higher brain/carcass weight ratio, so they develop ketosis more rapidly than adults. Is this a harmful process? No, more likely an evolutionary adaptation which supports the brain.

ketones age

The brain of newborn babies consumes a huge amount of total daily energy, and nearly half comes from ketones.  A week or so later, even after the carbohydrate content of breast milk increases, they still don’t get “kicked out of ketosis” (Bourneres et al., 1986).  If this were a harmful state, why would Nature have done this?  …and all those anecdotes, like babies learn at incredibly rapid rates… coincidence?  Maybe they’re myths.  Maybe not.




 

Ketosis in the animal kingdom

Imagine a hibernating bear: huge adipose tissue but small brain fuel requirement relative to body size and total energy expenditure.  No ketosis, because brain accounts for less than 5% of total metabolism.  In adult humans, this is around 19-23%, and babies are much higher (eg, Cahill and Veech, 2003Hayes et al., 2012).

 

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Discordant insulin sensitivity on a high protein diet

So, we have another “high protein” weight loss study (Smith et al., 2016).  Or really, a “low (0.8 g/kg) vs. moderate (1.2 g/kg) protein weight loss study.”  In brief, it took ’em about 6 months to lose 10% of their starting body weight, then were given 4 weeks of weight stability before “after” measurements were taken.

Important: this was not a contest to see who would lose more weight; they kept going and adjusting food intake until both groups lost 10%.  Not really ad lib, but otherwise a good study design imo.  The intervention was relatively weak (eg, protein 0.8 vs. 1.2 g/kg), but on the plus side, that’s realistic and very “do-able.”  If you’re interested in super-high protein diets (3-4 g/kg), check out research by Jose Antonio.

 




 

Big yet not unexpected finding: the low protein group lost about twice as much muscle than the normal protein group.

 

fat-free-mass

 

The isocaloric normal protein group lost more fat and less muscle than the low protein group.

But then everyone freaked out because the low protein group experienced a significant improvement in muscle/liver insulin sensitivity whereas the normal protein group didn’t:

 

glucose-rate-of-disappearance

 

-The headlines were hilarious, like, “high protein makes weight loss not work anymore.”

-Then some critics jumped the shark and blamed it on “liquid calories,” because whey protein shakes are totes non-Paleo, and #JERF.

-TBH, I found more interesting the changes in adipose insulin sensitivity

The normal protein group had the most insulin sensitive adipose of all groups… yet they lost more fat mass despite eating just as much or even slightly more than the other groups.

 

adipose-insulin-sensitivity

 

Does this mean they’re doomed to regain the weight?  I don’t think so, as high dietary protein is one of the strongest predictors of weight loss success long-term.

HERESY!  the low protein group had: 1) lower basal insulin than the normal protein group; 2) lower adipose insulin sensitivity; 3) ate less (NS); yet lost less fat mass.

 




 

In other words, the normal protein group had higher basal insulin, more insulin sensitive adipose tissue, and slightly higher food intake (NS).  According to the insulin model, they should’ve lost less fat mass than the low protein group, but they didn’t.

Is this another chink in the armor of the insulin model?

The truth seems to be: people lose weight on both LC and LF diets by giving up junk food.  On LC, this is accomplished by giving up carbs; on LF, this is accomplished by switching to better carbs.  Some people adhere better to one diet or the other.  Maybe insulin sensitivity has something to do with it.

Insulin from high protein: not bad?
Insulin from good carbs: not bad?
Junk food: no bueno.
So maybe just maybe it’s not just ze insulin…

 




 

Back to the protein…

This was not sorcery; it’s been seen before in a variety of different paradigms: dietary protein has a profound impact on nutrient partitioning.

Yes, even when it’s liquid calorie insulinogenic whey protein isolate bro-shakes.

Yes, even when it’s not crazy-high levels of protein…  seriously, 1.2 g/kg is not “high”

 

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Past blog posts on [the non-sorcery of] dietary protein:

Holiday feasts, the freshman 15, and damage control

Dietary protein, ketosis, and appetite control.

Nutrient Partitioning: …a *very* high protein diet.

Protein “requirements,” carbs, and nutrient partitioning

Cyclical ketosis, glycogen depletion, and nutrient partitioning

Meal frequency, intermittent fasting, and dietary protein

Muscle growth sans carbs

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“Afternoon diabetes” and nutrient partitioning

Don’t exacerbate afternoon diabetes with afternoon carbs.

Skeletal Muscle
As discussed previously [at length], insulin sensitivity in skeletal muscle follows a circadian pattern: starts out high in the morning and wanes throughout the day.

Diurnal variation in oral glucose tolerance: blood sugar and plasma insulin levels, morning, afternoon and evening (Jarrett et al., 1972)

 

impaired circadian glucose tolerance in the morning

 

Diurnal variation in glucose tolerance and insulin secretion in man (Carroll and Nestel, 1973)

Circadian variation of the blood glucose, plasma insulin and human growth hormone levels in response to an oral glucose load in normal subjects (Aparicio et al., 1974)

Adipose Tissue
And insulin sensitivity of adipose tissue goes in the opposite direction: starts out low, and increases as the day progresses.

Diurnal variations in peripheral insulin resistance and plasma NEFA: a possible link? (Morgan et al., 1999)
The studies were standardized for a period of fasting, pre-test meal, and exercise… Following insulin, NEFA fell more slowly in the morning (149 uM/15 min) than in the evening (491 uM/15 min).

Diurnal variation in glucose tolerance: associated changes in plasma insulin, growth hormone, and non-esterified fatty acids (Zimmet et al., 1974)
Adipose tissue insulin sensitivity is greater in the evening.  FFA are higher, and get shut down more rapidly, after a carb meal in the evening.

Summary: to minimize blood glucose excursions and proclivity for fat storage, eat more calories earlier in the day; this is circadian nutrient timing.  And according to the Alves study, a low-carb protein-rich dinner best preserves lean tissue during weight loss.

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Circadian phase delays and metabolism

Remember the “jet lag-resistant” mice?  Guess what: screw with circadian biology and metabolism pays the price.

In brief, vasopressin was classically thought of as an anti-hypotensive hormone.  The vasopressin analog Desmopressin is used to treat bed-wetting.  But vasopressin biology is much more interesting than that: mice lacking both vasopressin receptors require very little time adapting to large circadian phase changes.  And as with many fundamental concepts in chronobiology, this is intimately linked with metabolism.

People with certain polymorphisms of the vasopressin receptor, V1A, exhibit elevated blood glucose levels and are at greater risk for diabetes (Enhorning et al., 2009):

genotype

This risk is strongest in men in the highest quartile of fat intake, and is statistically more significant after adjusting for age and physical activity:

Fat consumption

This study wasn’t designed to be a very powerful indicator of diet-disease relationships, but a little speculation: some think higher fat [and lower carb] intake should be protective against diabetes… which may be true, for people who can tell time.  Alter one nucleotide in the vasopressin 1A receptor gene and the game changes.

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Circadian disruptions impact behavior and metabolism in a tissue-specific manner.

The control of circadian gene expression is complex, with layer upon layer of suppressors and enhancers, numerous transcription factors, and a lot of interactions.  A gross oversimplification: Clock and Bmal1 are positive regulators of circadian gene expression; Per and Cry are negative (you don’t really need to know any of this).

 

Some pretty cool progress has been made in examining the effects of global and tissue-specific deletion of circadian rhythm-related transcription factors.  Bear with me 🙂

For example, global Bmal1 knockout mice (ie, mice that don’t express Bmal1 anywhere in their whole body.  Zero Bmal1.  Nil.) (Lamia et al., 2008).  These mice are obese, and exhibit impaired glucose tolerance yet improved insulin sensitivity.

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On resistant starch and blood glucose control

For overall health and well-being, fermented foods like sauerkraut and kefir are great.  Especially when following a low carbohydrate diet which is generally low in the types of foods which feed the gut microbiome.

For those with gastrointestinal problems, the gut microbiota is probably involved.  Whether it is bacterial overgrowth or dysbiosis, gut bugs are usually the culprit.  Treatment options vary widely, ranging from global extermination with vinegar & a low fibre diet (as per Jane Plain), or remodeling the microbiome with a prebiotic like galactooligosaccharides.   Probiotics like bifidobacteria can help, too, if they’re administered with either prebiotics or fermented foods (they need something to nourish them in transit).  Dark chocolate is also an excellent vessel.  Resistant starch is another option, although the question remains as to whether or not this is compatible with a low carbohydrate diet.

Resistant starch has been around for a while, and when I was in school it received about 10 minutes of attention during the fibre lecture.  But Jimmy Moore and Richard Nikolay have been talking about it a lot lately so I decided to freshen up on the topic.  In brief, it can be therapeutic for GI issues, but some studies have shown mixed effects on glucose & insulin metabolism.  The former is virtually unarguable, but I found the latter interesting.  And the impact of resistant starch on ketosis is included as well.

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Low carbohydrate diets favorably impact testosterone levels.

It is known.  Carbohydrate restriction improves (lowers) testosterone in women with PCOS.  It works for men, too… but by “works” I mean “increases.”

Decrease of serum total and free testosterone during a low-fat high fibre diet (Hamalainen et al., 1982) 

Intervention pseudo-crossover study: 30 healthy Finnish men in their 40’s were studied on their habitual high fat diet (40%  fat), then put on a low-fat (25%) high fibre diet for 6 weeks, then switched back to high fat.  The high fat diet was also higher in saturates, P:S ratio 0.15 vs. 1.25.

free T

 

Free testosterone levels declined on the low fat diet, but they recovered after 6 weeks of going back to their high [saturated] fat dieting (p < 0.01).

Some observational data: Testosterone and cortisol in relationship to dietary nutrients and resistance exercise (Volek et al., 1997)

…fat, and in particular saturated fat, is associated with increased testosterone levels [in men]:

observational

 

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Physiological Insulin Resistance in Circadia

If you haven’t read Petro Dobromylskyj’s posts about Physiological Insulin Resistance, then just go do it.  Highly recommended.
I’ve written about it as well, albeit in a slightly different context:
What is our proper “natural” diet?
40 years ago a group of researchers turned ketosis into poetry.

But now on to more pressing matters.  In the food deprived state, Physiological Insulin Resistance develops, in part, to spare muscle (yea yea yeah and glucose for the brain).  But how much of this is due to ‘food deprivation’ per se as opposed to something else… like circadian rhythms.

Exhibit A. Hat tip to Dr Kruse for writing about this TED talk.  In it, Jessa describes a crab that lives on the beach; scurries up the beach when the tide comes in and back down when it goes out.  Scientists captured a few, flew them halfway around the world and put them in little tilted cages.  The crabs still scurried up & down, in time with the tides.

Exhibit B. Evidence that the lunar cycle affects human sleep.  People tend to sleep a little less during the full moon.  Subjects were recruited to a windowless sleep lab and had no exposure to sun/moon/anything outside – they maintained this circadian rhythm for 3 days  (Cajochen et al., 2013).  Different from the crabs, but similar (in a way).

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